International Journal of

Environmental Research
and Public Health

Review
Contribution of Genetic Polymorphisms in Human Health
Pieranna Chiarella * , Pasquale Capone and Renata Sisto

Department of Occupational and Environmental Medicine, Epidemiology and Hygiene, INAIL Research,
Via Fontana Candida 1, Monteporzio Catone, 00078 Rome, Italy
* Correspondence: p.chiarella@inail.it; Tel.: +39-0694181472

Abstract: Human health is influenced by various factors; these include genetic inheritance, behavioral
lifestyle, socioeconomic and environmental conditions, and public access to care and therapies in case
of illness, with the support of the national health system. All these factors represent the starting point
for the prevention and promotion of a healthy lifestyle. However, it is not yet clear to what extent these
factors may actually affect the health of an entire population. The exposures to environmental and
occupational factors are several, most of which might be poorly known, contributing to influencing
individual health. Personal habits, including diet, smoking, alcohol, and drug consumption, together
with unhealthy behaviors, may inevitably lead people to the development of chronic diseases,
contributing to increasing aging and decreasing life expectancy. In this article, we highlight the role of
susceptibility biomarkers, i.e., the genetic polymorphisms of individuals of different ethnicities, with
particular attention to the risk factors in the response to specific exposures of Europeans. Moreover,
we discuss the role of precision medicine which is representing a new way of treating and preventing
diseases, taking into account the genetic variability of the individual with each own clinical history
and lifestyle.

Keywords: health; disease; lifestyle; genetic variability; environment; risk factor; precision medicine

1. Introduction
Citation: Chiarella, P.; Capone, P.; In the year 2020, over 4 million new cancer cases and 1.9 million cancer-related deaths
Sisto, R. Contribution of Genetic were estimated in Europe. These data, found in the same year, have a key role to assess
Polymorphisms in Human Health. and monitor cancer-control measures across Europe [1]. In general, half of the overall
Int. J. Environ. Res. Public Health 2023, cancer diagnoses have been identified as breast, colorectal, lung, and prostate, while
20, 912. https://doi.org/10.3390/ the most cancer incidences were found in the female breast and the male prostate [2].
ijerph20020912 Collectively, all these four cancers account for half of the overall cancer burden in the
Academic Editor: Paul B. European population, although in terms of death, the most common causes of cancer
Tchounwou have been recognized in the lung, colorectal, breast, and pancreas. If we have a look at
the life of older people in Europe, we see that the variability of life expectancy is not
Received: 7 October 2022 identical in both genders. This difference between men and women has the tendency to
Revised: 16 December 2022
disappear after reaching 80 years of age. Furthermore, men and women seem to have
Accepted: 17 December 2022
different susceptibilities to disease, confirming that female life expectancy exceeds that
Published: 4 January 2023
of males in all European countries [3,4]. Apart from cancer, the main causes of death are
circulatory diseases, followed by respiratory diseases [5]. Cardiovascular disease remains
the most common cause of death worldwide and the most common cause of death in
Copyright: © 2023 by the authors.
Europe (Figure 1). Previous studies have reported that cardiovascular disease kills nearly
Licensee MDPI, Basel, Switzerland. four million people in Europe every year, approximately 44% of all deaths, with ischemic
This article is an open access article heart disease accounting for 44% of these cardiovascular deaths and stroke accounting for
distributed under the terms and 25% [6].
conditions of the Creative Commons In elderly people, we also assist with several comorbidities, including neurological
Attribution (CC BY) license (https:// disorders such as senile dementia, Alzheimer’s, and Parkinson’s disease. Alzheimer’s dis-
creativecommons.org/licenses/by/ ease accounts for 60% of all dementias. This pathology is considered a chronic degenerative
4.0/). disease in the general population and has been defined by the World Health Organization

Int. J. Environ. Res. Public Health 2023, 20, 912. https://doi.org/10.3390/ijerph20020912 https://www.mdpi.com/journal/ijerph
Int. J. Environ. Res. Public Health 2023, 20, 912 2 of 15

(WHO) as a deterioration in cognitive function [7]. At present, this morbidity has been
considered a global public health priority. In 2015, 47 million people affected by a form
of dementia were estimated in the world, over 1 million 200 thousand in Italy, with a
prevalence in the over 65-year-old population of 4.4%. The prevalence of this pathology
increases with age and is higher in women. In Italy, the prevalence in women ranges from
1.0% for the 65-69 age group to 30.8% for those over 90 years of age, compared to men,
whose
Int. J. Environ. Res. Public Health 2023, 20, x values vary from 1.6% to 22.1%, respectively, with about 900,0002 people
of 18 suffering
from dementia, 600,000 of which with Alzheimer’s disease [8,9].

Figure 1. Distribution of death for cardiovascular, ischemic, stroke, diseases.

Figure 1. Distribution of death for cardiovascular, ischemic, stroke, diseases.
In elderly people, we also assist with several comorbidities, including neurological
While it is easy to diagnose a specific disease in patients, it is much more difficult to
disorders such as senile dementia, Alzheimer’s, and Parkinson’s disease. Alzheimer’s dis-
identify a potential
ease accounts for 60% oforall
ongoing
dementias.disease in those ispeople
This pathology whoa are
considered daily
chronic exposed to several
degenera-
unknown
tive diseasetoxic
in theand dangerous
general population substances,
and has been in both environmental
defined and occupational
by the World Health Organi- contexts.
Although
zation (WHO) workplace exposureintocognitive
as a deterioration chemical and physical
function agentsthis
[7]. At present, is strictly
morbidity controlled
has to guar-
been considered
antee the respecta of global public
specific health priority.
Occupational In 2015, 47
Exposure million
Limits peopleitaffected
(OELs), by a
is fundamental to adopt
form
the of dementia
necessary were estimated
measures in the world,
to guarantee over 1 million
individual safety,200 thousand in
including Italy, with
personal protective and
a prevalence in the over 65-year-old population of 4.4%. The prevalence of this pathology
collective equipment such as gloves, helmet, mask, and waterproof shoes and suits, which
increases with age and is higher in women. In Italy, the prevalence in women ranges from
have been introduced to avoid the contamination with toxic substances as much as possible.
1.0% for the 65-69 age group to 30.8% for those over 90 years of age, compared to men,
Itwhose
mayvalues
be possible
vary fromfor1.6%
a subject
to 22.1%, torespectively,
be accidentally in contact
with about 900,000with
peopledangerous
suffering substances
present indoors. However, the human body
from dementia, 600,000 of which with Alzheimer’s disease [8,9]. has many other defenses that depend on the
presence of an efficient immune system, able to counteract any insult. Thanks
While it is easy to diagnose a specific disease in patients, it is much more difficult toto individual
identify a potential or ongoing disease in those people who are daily exposed
genetic inheritance, a subject will be able to repair potential damage by a variety of enzymes to several
unknownby
encoded toxic andown
their dangerous substances,
body, even though in the
botheffect
environmental and occupational
of the exposure may be poorlycon- known [10].
texts. Although workplace exposure to chemical and physical agents is strictly controlled
to guarantee the respect of specific Occupational Exposure Limits (OELs), it is fundamen-
2. Causative and Susceptibility Genes
tal to adopt the necessary measures to guarantee individual safety, including personal
The human
protective genome
and collective contains
equipment suchapproximately
as gloves, helmet, three
mask, billion base pairs,
and waterproof which reside in
shoes
the
and23 pairs
suits, which of chromosomes
have been introduced within the nucleus
to avoid of our cells.
the contamination withEach
toxic chromosome
substances contains
as much asto
hundreds possible. It mayofbegenes,
thousands possible for a carry
which subjectthe
to be accidentally for
instructions in contact
making with
proteins. Each
dangerous
of substances
the estimated present
30,000 indoors.
genes in theHowever,
humanthe human forms
genome body has anmany
average otherofde-
three proteins
fenses that depend on the presence of an efficient immune system, able to counteract any
(National Human Genome Research Institute). Scientists have already discovered many
insult. Thanks to individual genetic inheritance, a subject will be able to repair potential
functions
damage byof specific
a variety genes and
of enzymes the effects
encoded by theirassociated
own body, evenwiththough
variation in the
the effect human genetic
of the
code. It is well known
exposure may be poorly known [10]. that genetic variations underlie the great phenotypic diversity
that we know well, such as eye and hair color, and not just physical traits. Therefore,
2. Causative
there and Susceptibility
is no doubt that genes Genes
also contribute to modifying our character, personality, and
vulnerability, considering alsoapproximately
The human genome contains the influence of epigenetic
three factors,
billion base pairs, i.e.,reside
which DNA in methylation
the 23 pairs of chromosomes within the nucleus of our cells. Each chromosome
histone modifications and microRNA expression transmitted by parents to children. contains
hundreds to thousandsof
The variability of genes
genes, which carry the
in humans is instructions
widely known,for making
as theproteins. Each in the phe-
differences
of the estimated 30,000 genes in the human genome forms an average of three proteins
notype among individuals are strictly related to the genotype, which is inherited from
(National Human Genome Research Institute). Scientists have already discovered many
functions of specific genes and the effects associated with variation in the human genetic
Int. J. Environ. Res. Public Health 2023, 20, 912 3 of 15

ancestors and depends also on specific ethnicities [11]. When the genetic basis of diseases
is taken into consideration, it is possible to distinguish two types of genes: the causative
and susceptibility genes. The causative genes are those that, if present in an altered form
(i.e., a mutation), develop the associated pathology. This is the case, for example, of certain
familial forms of Alzheimer’s dementia where only 5% of cases are linked to mutations of
known genes, so the presence of the mutated allele is necessary and sufficient to develop
the pathology condition [12]. In the case of the susceptibility genes, the presence of a
defective “allele variant” of a gene does not mean the individual will necessarily develop
the disease, but it will be more likely to develop it rather than in other individuals that do
not have it. It is clear that other factors, such as genetics and environment, will contribute
to causing some individuals to develop the disease while others do not. This is the case,
for example, for the epsilon 4 allele of the apolipoprotein E (APOE) gene involved in fat
metabolism where a subtype of the APOE gene is involved in Alzheimer’s disease and
in cardiovascular diseases [13]. In fact, it was more frequent in patients with sporadic
Alzheimer’s disease (in those patients who account for 95% of Alzheimer’s cases) but
it is also present in healthy individuals who will never experience Alzheimer’s in their
lifetime. In the case of Alzheimer’s, the presence of the mutated allele is neither a necessary
nor sufficient condition for the manifestation of the disease [14]. In the last 30 years, gene
polymorphisms have raised a lot of interest in many scientific fields related to both public
health and disease. Gene polymorphisms are the most common type of genetic variation
in humans. They are present in the human population at a frequency higher than 1% and
differ from DNA mutations which are generally observed at extremely low frequencies and
in a restricted number of individuals. Genetic polymorphisms are important contributors
to interindividual variation since they have been investigated as useful biomarkers in the
medical context as well as in the study of pathology, epidemiology, pharmacology, clinical
immunology, and ethnicity. While gene mutation is rare and generally known to cause a
genetic disease, gene polymorphisms are not necessarily associated with a specific disease [15].

3. Genetic Polymorphisms as Biomarkers of Susceptibility

Humans are exposed to a wide variety of environmental and occupational factors
throughout their lifespan. These include both naturally occurring toxins and chemical
toxicants like pesticides, herbicides, chemicals, and industrial products, most of which
have been implicated as possible contributors to human disease susceptibility. In the case
of the occupational setting, the dangerous substances are well known and manipulated
with strict control, while according to the latest data, it has been estimated that about
24% of all diseases in the world are due to environmental factor exposure. Much of these
risks could be avoided through targeted interventions, as confirmed by the World Health
Organization report (WHO) entitled “Preventing Disease through healthy environments:
towards an estimate of the environmental burden of disease” [16]. To give an example,
the subjects could be exposed to a mixture of pesticides or a combination of neurotoxic
chemical solvents used in several industries such as in transportation, mining, construction,
manufacturing, and shipbuilding, whose applications vary from being used individually
or in the form of a mixture, such as in glues, paints, and cleaning products. That said, gene
polymorphisms have the power to identify susceptible subgroups in exposed populations,
and if we know exactly the polymorphism function, it might be possible to identify a
population at risk, due to the different allele frequencies among ethnic groups. However,
if a single genetic trait can be associated with an increased risk in specific individuals or
populations, these traits should be studied to evaluate the probability of contributing to the
risk of developing a disease [17]. In our former study, we investigated the susceptibility
risk in four ethnic populations, i.e., Africans, East Asians, Europeans, and South Asians,
predicting a model to assess the susceptibility among such subgroups. In such context,
we considered the most common genetic polymorphisms involved in the exposure of
occupational settings. In particular, we analyzed the gene polymorphisms involved in the
metabolism, i.e., (1) detoxification; (2) oxidative stress; (3) DNA damage’s repair [18]. Our
Int. J. Environ. Res. Public Health 2023, 20, 912 4 of 15

previous findings reported different susceptibilities in the four ethnicities, demonstrating

the highest relative risk related to the genes of detoxification, and oxidative stress was
found in the South Asian population, and the highest risk, associated with the DNA repair
gene, was instead observed in the Caucasian ethnic group [17,18]. The ethnicity to which
the individual belongs contributes to the difference in the response to the exposure.

3.1. Genetic Polymorphisms and Differences in the Metabolism

There is a relationship between the genetic predisposition of an individual and their
ability to metabolize a substance. Differences in drug metabolism can lead to severe toxicity or
therapeutic failure due to a change in the ratio between the drug dose and the concentration
of pharmacologically active substances in the blood as a result of genetic modifications [19].
Genetic polymorphisms of drug-metabolizing enzymes give rise to distinct subgroups in the
population that differ in their ability to perform certain drug biotransformation reactions [20].
In general, five distinctive groups of metabolizers have been identified:
(1) The extensive metabolizer (EM) typical of the normal population. These subjects
are either homozygous or heterozygous for the wild-type allele and have a normal
metabolism;
(2) The slow metabolizer phenotype (SM) that is associated with the accumulation of
specific drug substrates in the body, inherited as a recessive autosomal trait due to the
mutation or deletion of both alleles showing a slow metabolism. In some patients, the
drug is metabolized very slowly, accumulating the substance in the bloodstream;
(3) The poor metabolizers (PM) carry two defective alleles, showing a complete absence
of activity. The higher body concentration of the substance may cause adverse effects
due to the substance accumulation;
(4) The rapid metabolizers (RM) clear the drug very quickly, and the therapeutic con-
centration of the drug in the blood and tissues may not be reached. That means the
subject should have a higher dose to produce an effect;
(5) The ultra-extensive metabolizer (UEM) is characterized by enhanced drug metabolism
due to gene amplification inherited as an autosomal dominant trait. Individuals with
the ultra-extensive phenotype are prone to therapeutic failure because the drug con-
centrations in the plasma at normal doses are by far too low (faster metabolism) [21].
Here, we distinguish the most common behavioral habits in the following categories.

3.2. Metabolism of Drug

Drug metabolism describes the biotransformation of pharmaceutical substances in the
body so that they can be eliminated more easily. The majority of metabolic processes in-
volving drugs occur in the liver, as the enzymes that facilitate the reactions are concentrated
there. The rate of drug metabolism can vary significantly for different patients. For instance,
the CYP2D6 enzyme is responsible for the oxidative metabolism of 20–25% of drugs. The
CYP2D6 iso-enzyme is by far the most extensively characterized enzyme from the CYP450
superfamily, which exhibits a polymorphic expression in humans. It accounts for not more
than 2.6% of CYP450 in the liver and plays a very important role in the metabolism of
almost a hundred of the most commonly used drugs [22].

3.3. Metabolism of Smoke

Tobacco consumption represents the main etiological factor in lung carcinogenesis and
lung cancer is the most frequent malignant neoplasm in many countries. Other factors such
as individual genetic susceptibility, environmental and occupational exposures, stressful
life, poor diet, and many other factors may influence the quality of life of individuals.
The European directive on the smoking ban was passed by the European Parliament and
Council in 2003. The entry into effect of the EU’s Tobacco Advertising Directive occurred
on 31 July 2005 (World Bank Report on the Economics of Tobacco Control, 1999) https:
//ec.europa.eu/commission/presscorner/dtail/en/IP_05_1013 (accessed on 2 September
2022) [23]. In the USA the main cancer-related cause of mortality worldwide in both genders
Int. J. Environ. Res. Public Health 2023, 20, 912 5 of 15

accounts for an estimated 27% of total cancer deaths in 2015 and 20% in the EU in 2016 [24,25].
Nicotine is the primary psychoactive constituent of tobacco. Despite it is not a carcinogen,
this substance is involved in smoking in addition to the continuous exposure to toxic agents
present in tobacco smoke. Once inhaled, nicotine enters into the lungs by circulation to bind
to nicotinic cholinergic receptors. The dominant pathway of nicotine metabolism in humans
is the production of cotinine, which occurs in two steps. Cotinine is a nicotine metabolite
used to quantify exposure to active smoke, and especially to passive smoking. The CYP2A6
enzyme is responsible for the majority of nicotine metabolism and is classified into CYP2A6
genotypes with predicted phenotype groups, as described for the CYP2D6 in the above
paragraph [26]. Our analysis confirms that cancer risk due to smoking changes in different
ethnicities. Among cigarette smokers, African Americans and Native Hawaiians are more
susceptible to lung cancer than White people, Japanese Americans, and Latino people [27].

3.4. Metabolism of Ethanol

Dependence on alcohol may cause liver disease with a progressive inflammatory
process. In particular, alcoholics may undergo hepatic steatosis, a reversible condition
resulting in the accumulation of triglycerides in the liver. As a result, the individual may
undergo an increase in hepatomegaly. Other negative effects resulting from alcoholism
include cardiovascular disease, hypertension, lung inflammation, mood disorders, anxiety,
depression, and memory loss [28]. The most relevant enzymes of alcohol metabolism are
alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) with the contribution
of cytochrome P450 (CYP2E1). In general, ethanol is metabolized by alcohol dehydroge-
nase (ADH) and by aldehyde dehydrogenase (ALDH) enzymes, where acetaldehyde is
oxidized to acetate, while CYP2E1 metabolizes a small fraction of the ingested ethanol. The
coding variants in both of these genes seem to be protective, decreasing alcoholism risk
by increasing local acetaldehyde levels, either because ethanol is oxidized more rapidly or
because acetaldehyde is oxidized more slowly. The balance between the rates of ethanol and
acetaldehyde oxidation could be crucial in determining acetaldehyde concentrations within
cells, such that small differences in the relative activities of ADH and ALDH might produce
significant differences in acetaldehyde concentration [29]. The distribution of ADH1B and
ALDH2 coding variants changes greatly among different populations; for both genes, the
most common protective alleles are found in people of East Asian origin [30,31]. Variations
in genes encoding other ADH enzymes influence alcoholism risk in other populations.
For example, ADH4 variants strongly affect alcoholism risk in populations of European
descent. There are also non-coding variants that may affect the risk of alcoholism [29].
Although variations in individual ADH and ALDH genes can affect the risk of alcoholism,
we should think that one gene is not sufficient to determine the risk. Nonetheless, there are
many genes unrelated to ethanol metabolism which may affect the risk of being influenced
by multiple social and environmental factors. The level of ethanol consumption and the
risk of alcoholism mainly depends on the ADH or ALDH alleles. ADH1B and ALDH2
have been reported as the genes most strongly associated with alcoholism risk. A variant
of the ADH1B gene (rs1229984, i.e., Arg48His) has been reported to be associated with
reduced rates of alcohol and drug dependence. The allele with increased activity and higher
oxidation of ethanol to acetaldehyde is His48, encoded by rs1229984. Carriers with one or
two ADH alleles, such as (G/A) or (A/A) have a reduced risk of alcoholism, metabolizing
alcohol faster than carriers of the G/G genotype [32].
The most important information on the gene polymorphisms, relevant to the human
metabolism, is summarized in Table 1 below. Here, we have focused on three categories
of enzymes involved in the following functions: detoxification, oxidative stress, and
DNA repair damage. Altogether, they include some functional enzymes involved in
the metabolism of drugs, smoke, and ethanol, which affect the behavioral habits of many
individuals. Such enzymes, summarized below, have been classified according to their
specific function and allele frequency, showing specific effects depending on the amino
acid substitution occurring in the polymorphism.
Int. J. Environ. Res. Public Health 2023, 20, 912 6 of 15

Table 1. List of specific gene polymorphisms and relative enzymes relevant to the human metabolism.

Polymorphism Function Detoxification European Allele Frequency Effects on Enzyme Activity

Glutathione S Transferase
GST-T1
GST-T1 GST-M1 and GST-T1 homozygous deletions (pos/null) have a
A = 0.867
rs17856199 decreased ability to detoxify carcinogens, toxicants, and oxidative
C = 0.183
GST-M1 stress products. The gene deletion has been found in Caucasian and
GST-M1 Asian populations compared to Africans [33].
A = 0.488
rs366631
G = 0.512

Detoxification of xenobiotics, carcinogenic substances, The distributions of GSTA1-69C > T promoter haplotypes and
therapeutic drugs, environmental toxins, and oxidative diplotypes were significantly different among the human
GST-A1
GST-A1 stress products. populations. The frequencies of GSTA1-69C > T polymorphism were
A = 0.571
rs3957357 similar to those of the African American population and the
G = 0.429
populations with White ancestry, but significantly different from
those reported for the populations with Asian ancestry [34].
Several papers published findings associating GSTP1 Ile105Val
GST-P1
GST-P1 genotypes with bronchial, childhood, or atopic asthma. Compared
A = 0.669
rs1695 with the AA genotype, the GA + GG genotype decreased lung
G = 0.331
cancer susceptibility [35].
Epoxide hydrolase
In vitro polymorphisms in exons 3 (His113Tyr) and 4 (Arg139His)
EPHX1-Ex3: lead to reduced activity (slow allele) and increased activity
EPHX1-Ex_3 rs1051740 Biotransformation enzymes converting epoxides from the T = 0.696 (fast allele).
degradation of aromatic compounds to trans-dihydrodiols C = 0.304 T to C substitution (slow allele) reduces the enzyme activity.
excreted from the body. EPHX1 was shown to take part in EPHX1-Ex4: Decreased activity (histidine)
EPHX1-Ex_4 rs2234922 protection against oxidative stress. A = 0.836 A to G substitution (fast allele) increases the enzyme activity.
G = 0.164 Increased activity (arginine) [36].
Cytochrome P450 family
CYP1A1-2A:
CYP1A1_2A Catalysis of reactions involved in the drug metabolism and
A = 0.893 The CYP1A1 Ile462Val polymorphism may enhance the
rs4646903 synthesis of cholesterol, steroids, and lipids, some of which susceptibility to cervical cancer in Caucasian females. The gene has
G = 0.107
are found in cigarette smoke. The enzyme’s endogenous been associated with lung cancer risk. Higher inducibility. Increased
CYP1A1_2C CYP1A1-2C:
substrate is able to metabolize some polycyclic aromatic oxidation [37].
rs1048943 T = 0.965
hydrocarbons into carcinogenic intermediates.
Ile462Val C = 0.035
Int. J. Environ. Res. Public Health 2023, 20, 912 7 of 15

Table 1. Cont.

Polymorphism Function Detoxification European Allele Frequency Effects on Enzyme Activity

Cytochrome P450 2E1
The genotype distributions of CYP2E1*5B and *6 were similar to the
Caucasian population but were different from East Asian
CYP2E1*5B: populations. Wang, L.N.; Wang, F.; Liu, J.; Ying-Hui, J.; Fang, C.; Ren,
CYP2E1*5B Cytochrome P450 2E1 (CYP2E1) is one of the major G = 0.959 X.Q. CYP1A1 Ile462Val polymorphism is associated with cervical
rs3813867 enzymes involved in the metabolism and detoxification of A = 0.041 cancer risk in Caucasians not Asians: A Meta-Analysis. Front.
various drugs and xenobiotics. Physiol. 2017, 8, 1081.
https://doi.org/10.3389/fphys.2017.01081. [38]
CYP2E1*6:
CYP2E1*6 CYP2E1*6 polymorphism causes a reduction in CYP2E1 enzyme
T = 0.908
rs6413432 activity [39].
A = 0.091
Cytochrome P450 family 2 subfamily D6 and Cytochrome P450 family 2 subfamily A6
Unfunctional alleles represent 26% of the variability mainly
in CYP2D6*4.
CYP2D6:
CYP2D6 CYP2D6 is responsible for the oxidative metabolism of “Frequency of CYP2D6 Alleles Including Structural Variants in the
G = 0.710
rs16947 20–25% of drugs. United States” Del Tredici, A.L.; Malhotra, A.; Dedek, M.; Espin, F.;
A = 0.290
Roach, D.; dan Zhu, Guang.; Voland, J.; Moreno, T.;A. Front.
Pharmacol., 2018 Pharmacogenetics and Pharmacogenomics [40]
The frequencies of this allele vary considerably among different
ethnic populations, the deletion alleles being most common in
Oriental people (up to 20%). Studies of Japanese populations
Nicotine metabolism is mediated primarily by cytochrome CYP2A6:
CYP2A6 suggest that CYP2A6 poor metabolizer genotypes result in altered
CYP2A6. The genetic variation in this gene has been linked A = 0.973
rs1801272 nicotine kinetics and may lower cigarette smoking-elicited lung
with several smoking behavior phenotypes. T = 0.026
cancer risk, whereas similar studies in Caucasian populations have
not revealed any clear associations between variant CYP2A6
genotypes and smoking behavior or lung cancer predisposition [41].
Int. J. Environ. Res. Public Health 2023, 20, 912 8 of 15

Table 1. Cont.

Polymorphism Function Detoxification European Allele Frequency Effects on Enzyme Activity

N-Acetyl Transferase
N-acetyltransferase 1 detoxifies many drugs and chemicals
found in the environment eliminated from the body or
NAT-1:
NAT1 bioactivated to metabolites causing toxicity/cancer. NAT1
G = 0.974 NAT-1: a monomorphic form of the enzyme [42].
rs4987076 activity is regulated by genetic polymorphisms as well as
A = 0.025
environmental factors such as substrate-dependent
down-regulation and oxidative stress.
N-acetyltransferase 2 enzyme detoxifies xenobiotics
Multiple NAT2 alleles (NAT2*5,*6, *7, and *14) have substantially
(carcinogens and drugs). Variation at the NAT2 gene has NAT-2:
NAT2 decreased acetylation activity and are common in Caucasian people
been linked to the human acetylation capacity: slow, G = 0.434
rs1208 and populations of African descent. Link between acetylator
intermediate, and fast, which modifies susceptibility to A = 0.565
phenotype and increased risk for bladder and colon cancer [43].
cancer and adverse drug reactions.
Oxidative Stress
A study of 127 Finnish patients concluded that the rs2333227 allele
increased the risk of Alzheimer’s disease [44].
MPO:
MPO Myeloperoxidase In a further study polymorphism of MPO was statistically associated
Oxidoreductase catalyzing H2 O2 to H2 O. C = 0.910
rs2333227 with AD in a gender-specific manner. Myeloperoxidase
T = 0.089
polymorphism is associated with a gender-specific risk for
Alzheimer’s disease [45].
Heme Oxygenase Cytoprotective enzyme activated during cellular stress HO1:
In the Ala16Val, the Ala amino acid seems to be more favorable than
rs2071746 such as inflammation, ischemia, hypoxia, hyperoxia, A = 0.440
the Val amino acid. Higher risk for Alzheimer’s disease (TT) [46].
-413AT and radiation. G = 0.560
SOD: Ala16Val: The Val amino acid is less favorable. Association of
SOD2 Mitochondrial enzyme with a key role in protecting the cell
A = 0.502 smoking and homozygosity for the MnSOD Val allele contributing
rs4880 from oxidative damage.
G = 0.498 to an increased risk of diabetic nephropathy [47].
The “G” and “T” alleles resulted in higher and lower expressions of
NRF2 rs6721961 NRF2 mRNA, showing that the G allele is beneficial for protection
NRF2
G = 0.875 (wt) from pathologies. In contrast, the “T” allele of rs6721961
rs6721961
T = 0.125 (mut) significantly increases susceptibility to the elevation of the hearing
Regulator of the cell transcriptional response to oxidative NRF2 rs6706649 threshold at 4 kHz in the occupational setting [48]. NRF2 (rs6721961)
NRF2
stress induced by exposure to xenobiotics. C = 0.882 (-617A/A) alleles in the NRF2 gene have been associated with
rs6706649
T = 0.118 female non-smokers with adenocarcinoma and are regarded as a
NRF2 rs35652124 prognostic biomarker for assessing the overall survival of patients
NRF2
C = 0.327 with lung adenocarcinoma [49].
rs35652124
T = 0.672 “C” indicates the wild allele, and “T” indicates the mutant allele [50].
Int. J. Environ. Res. Public Health 2023, 20, 912 9 of 15

Table 1. Cont.

Polymorphism Function Detoxification European Allele Frequency Effects on Enzyme Activity

NQO1 rs1800566: The variant enzyme, C609T, is ubiquitinated by the proteasome
NQO1 Enzyme involved in preventing free-redox
G = 0.809 (greater risk for 609TT). Susceptibility risk for hepatocellular
rs1800566 radical generation.
A = 0.190 carcinoma [51].
NQO1 rs1131341 The variant enzyme C465T shows reduced enzyme activity.
NQO1 (C465T, Arg139Trp) is a polymorphism within NQO1
G = 0.961 Potential risk of (ALL) Acute Lymphoblastic Leukemia (AML) Acute
rs1131341 (NAD(P)H dehydrogenase (quinone 1)
A = 0.038 Myeloid Leukemia [52].
DNA damage Repair
In solid tumors, the genotypes CG and/or GG at hOGG1 rs1052133
The human 8-oxoG DNA glycosylase 1 plays a central role have been reported to be associated with an increased risk of various
in repairing 8-oxoGs via the base excision repair pathway. hOGG1 types of cancer. The polymorphic site of hOGG1, i.e., rs1052133
hOGG1
Evidence suggests that hOGG1 affects the activity as a C = 0.778 (Ser326Cys), C to G showed that the glycosylase activity of the “G”
rs1052133
genetic marker for the prediction of personal susceptibility G = 0.221 variant is more sensitive to inactivation by oxidizing agents than
to several cancers. that of the “C” wild-type, and cells carrying the “G” allele may
accumulate mutations more readily under oxidative stress [53].
XRCC1 XRCC1
rs25487 The protein encoded by XRCC1 is involved in the repair of C = 0.642 XRCC1 has protective gene polymorphisms due to the enhanced
Arg399Gln DNA single-strand breaks formed by exposure to ionizing T = 0.357 repair activity even though the Arg399Gln polymorphism (rs25487
rs1799782 radiation and alkylating agents. G = 0.937 and rs1799782 Arg194Trp) have been reported to be related to
Arg194Trp A = 0.062 prostate cancer [54].
XRCC3 promotes the homology-directed repair of DNA damage in
The gene is involved in the homologous recombination mammalian cells. Three amino acid substitution variants of DNA
XRCC3
XRCC3 repair pathway (HRR) of double-stranded DNA, deputed repair genes (XRCC1 Arg194Trp, XRCC1 Arg399Gln, and XRCC3
G = 0.617
rs861539 to repair chromosomal fragmentation, translocations, Thr241Met) showed an association with breast cancer susceptibility.
A = 0.382
and deletions. Polymorphisms of XRCC1 and XRCC3 genes and susceptibility to
breast cancer [55].
The ERCC2 contributes to the synthesis of XPD protein. XPD protein is involved in transcription initiation and in the control
XPD/ERCC2
XPD/ERCC2 This is an essential subunit of a group of proteins known as of the cell cycle and apoptosis. The ERCC2-rs13181 C allele was
T = 0.626
rs13181 the TFIIH complex with two major functions: the activation associated with a significantly increased risk of colorectal cancer
G = 0.373
of gene transcription and the repair of damaged DNA. risk [56].
Int. J. Environ. Res. Public Health 2023, 20, 912 10 of 15

Table 1. Cont.

Polymorphism Function Detoxification European Allele Frequency Effects on Enzyme Activity

Alcohol dehydrogenase
ADH1B has been reported to associate with reduced rates of alcohol
and drug dependence. The allele with increased activity, meaning
the more rapid oxidation of ethanol to acetaldehyde, is His48,
encoded by rs1229984. Carriers with one or two ADH alleles, such
ADH1B ADH1B
as (G/A) or (A/A) have a reduced risk for alcoholism. These
rs1229984 G = 0.951
findings support that the His allele can greatly lower the risk of AD
Arg 48 His A = 0.048
and alcohol abuse and provide strong evidence for the involvement
Enzymes involved in alcohol metabolism. The functional
of the ADH1B gene in the pathogenesis of AD and alcohol-induced
variant, Arg48His (rs1229984), is located in the ADH1B
diseases in particular in multiple populations such as Asian
gene and protects against alcohol dependence.
populations [57].
ADH1B ADH1B ADH1B Arg370Cys is monomorphic in European populations, but it
rs2066702 G = 0.997 has been shown to have a small effect on the rate of alcohol
Arg370Cys A = 0.002 elimination in African Americans [58].
An increasing number of studies have investigated the association
between ADH polymorphisms and cancer risk in humans. AA
ADH1C The rs698(A) allele is the most common, encoding ADH1C normal enzyme activity AT-TT reduction in the enzyme activity and
rs698 isoleucine; the rare (T) allele encodes the A = 0.609 intolerance to ethanol. Among them, studies of the ADH1C
Ile350Val variant phenylalanine T = 0.391 Ile350Val (rs698) variant accounted for more than others. The results
indicate that ADH1C Ile350Val polymorphism may contribute to
cancer risk among African populations and Asian populations [59].
The alcohol dehydrogenase (ADH) family represents one
A significantly increased risk of developing esophageal
of the key sets of enzymes responsible for the oxidation of ADH4
ADH4 squamous-cell carcinoma was revealed in subjects with the AA
alcohol. This enzyme is an important member of this A = 0.998
rs3805322 genotype for rs3805322 (ADH4) compared with those with the AG
family, it is a functional candidate for alcohol dependence G = 0.003
or GG genotype [60].
in human consumption of alcohol.
Aldehyde dehydrogenase
Aldehyde dehydrogenases efficiently oxidize and, in most
ALDH2 Individuals with the ALDH2 504Lys variant were less associated
instances, detoxifies a significant number of chemical ALDH
rs671 with alcoholic liver disease compared to those with ALDH2 504Glu
aldehydes which otherwise would be harmful to G = 1.000
Glu504Lys by genotypic and allelic analyses [61].
the organism.
Int. J. Environ. Res. Public Health 2023, 20, 912 11 of 15

4. Discussion
The genome of each individual interacts with exposures to many environmental and
occupational agents, including personal habits, such as diet, drug consumption, alcohol,
and smoking. When a pathology by chance develops, all these factors influence several
aspects of a complex response exerted by the human being: the age of onset, the rate of
progression, and the therapies and side effects following medical treatments [62]. The
actual knowledge of genetics that has been influenced by genome and environmental mod-
ifications will contribute to diagnosing and treating diseases in more precise and effective
ways. The recent progress in medicine supported by novel technologies is developing
fast, modifying the concepts and ideas to treat diseases. In the last thirty years, precision
medicine started to emerge representing a new way to prevent aging and disease, taking
into account many factors, i.e., the age, the genetic variability of the individual, the clinical
history, the personal lifestyle and habit, and the effect of pharmacological treatments [63].
This novel concept is changing our perspective in terms of therapy and screening. If the
traditional protocols for diagnostics and therapeutics have been generally structured on the
basis of the average patient, precision medicine now shows a different perspective, in which
the variability of the population and ethnicity include advancements in genome sequencing,
allowing the discovery of novel mutations and other functional genes [64]. These polymor-
phic genes represent a group of susceptibility biomarkers for selected subgroups sharing
common genetic characteristics [65]. The variability in the population represents a critical
issue to develop targeted therapeutic protocols to treat diseases. In the study of disease,
we need a global assessment that takes into account not only the clinical and instrumental
examinations but also the patient’s history, familiarity, and lifestyle, together with all the
factors affecting the progression of the disease and the response to treatment. Thanks to the
identification of specific biomarkers, such as the biomarkers of exposure and effects in the
occupational context, the risk of developing a certain disease can be earlier identified. This
allows to improve preventive strategies or treatments that, if implemented early, will be
more effective to treat disease supported by reliable diagnostic tests that will help to choose
the best treatment. For instance, the analysis of the biological characteristics of a malignant
tumor will allow to select patients who will benefit from personalized treatment. If this is
not the case, the patient will be addressed immediately to alternative therapies. Reducing
the side effects of a drug and adverse reactions is another goal. Pharmacogenetics tests
may help to provide safe treatments with few adverse effects for the individual, taking into
account the genetic profile. For instance, depending on the variant allele of polymorphism,
the drug will be metabolized more or less quickly. This can explain why some patients
will suffer from adverse effects, where the drug, poorly metabolized, is accumulating in
the body, while other patients will metabolize very quickly in the absence of an effect. The
reduction in the use of invasive tests in favor of safe molecular tests is another relevant
issue. There are also pathologies, diagnoses, and follow-ups of dangerous tests, including
biopsies, that are sometimes difficult to execute and too invasive for the patient. The use of
reliable and harmless biomarkers of exposure and effect is mandatory in order to improve
the quality of the patient’s life, choosing the most suitable biological matrix that should
be easy to harvest, such as in the case of urinary sediment, exfoliated buccal cells and
blood [66,67] matrices are not invasive, easy to harvest, facilitating the type of diagnosis.
For instance, the use of oral mucosa exfoliates represents a valid alternative [68]. Differently
from blood, the buccal cells are easy to harvest by self-made mouthwash or scraping, do
not require specialized staff or equipment, and ensure good DNA yield with a low risk [66].
However, the most relevant advantage of using blood is the plasma collection, useful for
biochemical analysis, and the harvesting of a high number of peripheral mononuclear
cells that may be used for several DNA analyses, including genetic polymorphisms and
molecular biology tests [69]. The only critical issue of blood accruing is the expertise of
the operator who should avoid pain and the risk of infection for the patient. On the other
hand, despite urine being rarely used for genotyping, due to the presence of a mixed cell
population (leukocytes, renal tubular, transitional urothelial, and squamous cells), there
Int. J. Environ. Res. Public Health 2023, 20, 912 12 of 15

are novel alternatives and useful kits to extract cells. However, no matter what biological
matrix is used for genetic analysis, urine sample collection is mandatory for the assessment
of internal dose biomarkers.

5. Conclusions
The effect of exposure to health hazards means that individuals and groups in the
population are more or less likely to develop diseases after a potentially dangerous expo-
sure. This condition, apparent or silent, is not only due to genetic inheritance but also to
individual behavior and personal habits. People are more or less used to consuming drugs,
drinking alcohol, and smoking [70]. In small amounts, the organism is able to detoxify the
substance, but there are people with poorly efficient metabolisms due to their inherited ge-
netic variability that differs from other individuals. Furthermore, the interethnic difference
in the consumption of certain substances might have severe adverse effects or no efficacy at
all, depending on the genotype. In the past, particularly around the year 1970, people did
not pay particular attention to keeping themselves healthy [71,72]. Common habits and
lifestyles changed many years later, when alcohol consumption, heavy smoking, and the
abuse of psychotropic drugs were reduced [73]. However, despite the current perception of
living with a correct habit and lifestyle, nobody can predict the duration of life expectancy.
The last decade has seen many advances in proteomics and genomics science, and precision
medicine emerged, representing a new concept of dealing with and preventing diseases,
taking into account the genetic variability of the individual, the clinical history, and the
lifestyle. Precision medicine is based on the decision to prescribe a specific drug suitable for
the individual’s genotype with the aim of maximizing the efficacy of the drug by mitigating
the risks of the ethnic group to which the patient belongs. In the absence of a genotyping
test, ethnicity is seen as a model of the patient’s probable genotype, based on the frequency
of genetic variations with some ethnic characteristics [68]. Precision medicine aims to
develop effective strategies for patient groups who share specific genetic and molecular
common traits. This novel science studies how the genetic structure of human beings
influences the action of drugs administered to patients, with the ultimate goal of predicting
and therefore preventing adverse reactions and/or therapeutic failures [74]. In particular,
there is a need for the right drug against a specific disease with the correct dosage for
patients who share common characteristics. The idea of precision medicine will change the
approach to the prevention, diagnosis, and treatment of diseases. This method involves
a significant change of perspective: traditional diagnostic and therapeutic protocols have
been generally structured on the basis of the “average patient”, while precision medicine
intends to take into account the variability of the population, in order to develop targeted
therapies for selected subgroups with common traits. The genetic variability of a popula-
tion, including the polymorphic genes presented in this article, becomes fundamental in
order to develop tailored therapeutic protocols. Anyway, the right drug should be available
at the right dose and to the right genotype. Recognizing the importance of interethnic
differences in drug response, it is not surprising that regulatory authorities will require the
adequate participation of various demographic subgroups of patients by gender, ethnicity,
and age in clinical trials. This is fundamental to assessing safety and efficacy data in these
subgroups [75,76].

Author Contributions: All the authors contributed to the elaboration of this manuscript. P.C. (Pier-
anna Chiarella); conceptualization, investigation of the research articles and polymorphisms, writing
of original draft preparation; P.C. (Pasquale Capone); analysis and study of selected scientific liter-
ature and contribution to manuscript and bibliography; R.S.; manuscript correction, editing, and
supervision. Authorship has been limited to those who have contributed substantially to the work
reported. All the authors gave their consent to publish this article and checked, commented, and
reviewed the manuscript prior to submission. All authors have read and agreed to the published
version of the manuscript.
Funding: This research received no external funding.
Int. J. Environ. Res. Public Health 2023, 20, 912 13 of 15

Institutional Review Board Statement: This study did not required ethical approval.
Informed Consent Statement: All the authors gave their consent to publish this article and checked,
commented, and reviewed the manuscript prior to submission.
Data Availability Statement: Genotype and allele frequencies have been down-loaded from the
Ensembl project of genome databases for vertebrates and other eukaryotic species http://grch37.
ensembl.org/Homo_sapiens/Variation, public database (accessed on 2 September 2022).
Acknowledgments: We thank Giovanna Tranfo for the opportunity to participate in the proposed
Special Issue.
Conflicts of Interest: The authors declare no conflict of interest.

References
1. Dyba, T.; Randi, G.; Bray, F.; Martos, C.; Giusti, F.; Nicholson, N.; Gavin, A.; Flego, M.; Neamtiu, L.; Dimitrova, N.; et al. The
European cancer burden in 2020. Incidence and mortality estimates for 40 countries and 25 major cancers. Eur. J. Cancer 2021, 157,
308–347. [CrossRef] [PubMed]
2. Kotwal, A.A.; Schonberg, M.A. Cancer screening in the elderly: A review of breast, colorectal, lung, and prostate cancer screening.
Cancer J. 2017, 23, 246–253. [CrossRef] [PubMed]
3. Barford, A.; Dorling, D.; Davey Smith, G.; Shaw, M. Life expectancy: Women now on top everywhere. BMJ 2006, 332, 808.
[CrossRef] [PubMed]
4. Chiarella, P.; Capone, P.; Sisto, R. Polymorphic genes and gender difference: Analysis of a European sample. Ital. J. Occup. Environ.
Hyg. 2021, 12, 156–166. [CrossRef]
5. OECD/European Union. Health at a Glance: Europe 2020: State of Health in the EU Cycle; OECD Publishing: Paris, France, 2020; pp.
1–237. [CrossRef]
6. Townsend, N.; Kazakiewicz, D.; Wright, F.L.; Timmis, A.; Huculeci, R.; Torbica, A.; Gale, C.P.; Achenbach, S.; Weidinger, F.; Vardas,
P. Epidemiology of cardiovascular disease in Europe. Nat. Rev. Cardiol. 2022, 19, 133–143. [CrossRef] [PubMed]
7. Gauthier, S.; Rosa-Neto, P.; Morais, J.A.; Webster, C. Journey through the diagnosis of dementia. In World Alzheimer Report 2021;
Alzheimer’s Disease International: London, England, 2021; pp. 1–313.
8. Jeorges, J.; Miller, O.; Bintener, C. Dementia in Europe Yearbook 2019: Estimating the Prevalence of Dementia in Europe; Alzheimer
Europe: Luxembourg, 2020; pp. 1–109, ISBN 978-99959-995-9-9. [CrossRef]
9. Regional Epidemiological Service and Epidemiological Data Registers. Available online: https://demenze.regione.veneto.it/
PDTA/dati (accessed on 2 September 2022).
10. Jackson, S.; Bartek, P.J. The DNA-damage response in human biology and disease. Nature 2009, 461, 1071–1078. [CrossRef]
[PubMed]
11. Orgogozo, V.; Morizot, B.; Martin, A. The differential view of genotype-phenotype relationships. Front. Genet. 2015, 6, 179.
[CrossRef] [PubMed]
12. Bekris, L.M.; Yum, C.-E.; Bird, T.D.; Tsuang, D. Genetics of Alzheimer disease. Am. J. Neuroradiol. 2010, 23, 213–227. [CrossRef]
13. Chouinard-Watkins, R.; Plourde, M. Fatty acid metabolism in carriers of Apolipoprotein e Epsilon 4 allele: Is it contributing to
higher risk of cognitive decline and coronary heart disease? Nutrients 2014, 6, 4452–4471. [CrossRef]
14. Tarawneh, R.; Holtzman, D.M. The Clinical Problem of Symptomatic Alzheimer Disease and Mild Cognitive Impairment. Cold
Spring Harb Perspect Med. 2012, 2, a006148. [CrossRef]
15. Giuffrè; Bianchi, A.; Gulotta, G.; Sartori, G. (Eds.) Role of behavioural and genetic factors. In Neuroscience Forensic Manual; Giuffrè:
Milan, Italy, 2009; pp. 69–90, ISBN 9788814148590.
16. Prüss-Üstün, A.; Corvalán, C.; WHO. Preventing Disease through Healthy Environments: Towards an Estimate of the Environmental
Burden of Disease; WHO: Geneva, Switzerland, 2006; ISBN 92 4 159382 2.
17. Chiarella, P.; Capone, P.; Carbonari, D.; Sisto, R. A predictive model assessing genetic susceptibility risk at workplace. Int. J.
Environ. Res. Public Health 2019, 16, 2012. [CrossRef]
18. Chiarella, P.; Capone, P.; Sisto, R. The Role of Genetic Polymorphisms in the occupational exposure. In The Recent Topics in Genetic
Polymorphisms; Caliskan, M., Erol, O., Öz, G.C., Eds.; Intech Open: London, UK, 2019; pp. 1–16.
19. Topic, E. The role of pharmacogenetics in management of cardiovascular disease. J. Int. Fed. Clin. Chem. Lab. Med. 2003, 14, 78–88.
20. Rommel, G.T.; Kim, R.B. Introduction to Clinical Pharmacology. In Clinical and Translational Science, 2nd ed.; Robertson, D.,
Williams, G., Eds.; Academic Press: Cambridge, MA, USA, 2016; pp. 365–388.
21. Belle, D.J.; Singh, H. Genetic factors in drug metabolism. Am. Fam. Physician 2008, 77, 1553–1560.
22. Ingelman-Sundberg, M. Genetic polymorphisms of cytochrome P450 2D6 (CYP2D6): Clinical consequences, evolutionary aspects
and functional diversity. Pharm. J. 2005, 5, 6–13. [CrossRef] [PubMed]
23. World Bank. World Bank Report on the Economics of Tobacco Control; World Bank: Washington, DC, USA, 1999.
24. Tobacco Advertising Ban Takes Effect 31 July. Available online: https://ec.europa.eu/commission/presscorner/detail/en/IP_05
_1013 (accessed on 3 July 2022).
Int. J. Environ. Res. Public Health 2023, 20, 912 14 of 15

25. Murphy, S.E. Nicotine metabolism and smoking: Ethnic differences in the role of P450 2A6. Chem. Res. Toxicol. 2017, 30, 410–419.
[CrossRef]
26. Derby, K.S.; Cuthrell, K.; Caberto, C.; Carmella, S.G.; Franke, A.A.; Hecht, S.S.; Murphy, S.E.; Le Marchand, L. Nicotine metabolism
in three ethnic/racial groups with different risks of lung cancer. Cancer Epidemiol. Biomark. Prev. 2008, 17, 3526–3535. [CrossRef]
27. Haiman, C.A.; Stram, O.D.; Wilkens, L.; Pike, C.M.; Malcolm, C.; Kolonel, L.N.; Henderson, B.E.; Le Marchand, L. Nicotine
metabolism in three ethnical/ratial groups with different risk of lung cancer. N. Engl. J. Med. 2006, 26, 333–342. [CrossRef]
[PubMed]
28. Patel, Y.M.; Park, S.L.; Han, Y.; Wilkens, L.R.; Bickeböller, H.; Rosenberger, A.; Caporaso, N.; Landi, M.T.; Brüske, I.; Risch, A.; et al.
Novel association of genetic markers affecting CYP2A6 activity and lung cancer risk. Cancer Res. 2016, 76, 5768–5776. [CrossRef]
29. Rehm, J. The risks associated with alcohol use and alcoholism. Alcohol Res. Health 2011, 34, 135–143.
30. Edenberg, H.; Foroud, T. The genetics of alcoholism: Identifying specific genes through family studies. Addict. Biol. 2006, 11,
386–396. [CrossRef]
31. Kitson, K. Regulation of Alcohol and Aldehyde dehydrogenase activity: A metabolic balancing act with important social
consequences. Alcohol. Clin. Exp. Res. 1999, 23, 955–957. [CrossRef] [PubMed]
32. Wall, T.; Luczak, S.E.; Hiller-Sturmhofel, S. Biology, Genetics and Environment: Underlying factor influencing alcohol metabolism.
Alcohol Res. Curr. Rev. 2016, 38, 59–68.
33. Edenberg, H.J. The genetics of alcohol metabolism: Role of alcohol dehydrogenase and aldehyde dehydrogenase variants. Alcohol
Res. Health 2007, 30, 5–13.
34. Rashidi, W.N.W.; Bakar, S.A. Glutathione S-Transferase: An overview on distribution of GSTM1 and GSTT1 polymorphisms in
Malaysian and other populations. Mal. J. Med. Health Sci. 2019, 15, 85–95.
35. Uckun Şahinoğulları, Z. Frequencies of glutathione S-transferase A1 rs3957357 polymorphism in a Turkish population. J. Surg.
Med. 2021, 5, 221–225. [CrossRef]
36. Xiao, J.; Wang, Y.; Wang, Z.; Zhang, Y.; Li, Y.; Xu, C.; Xiao, M.; Wang, H.; Guo, S.; Jin, L.; et al. The relevance analysis of GSTP1
rs1695 and lung cancer in the Chinese Han population. Int. J. Biol. Mark. 2021, 36, 48–54. [CrossRef]
37. Agudo, A.; Peluso, M.; Sala, N.; Capellà, G.; Munnia, A.; Piro, S.; Marín, F.; Ibáñez, R.; Amiano, P.; Tormo, M.J.; et al. Aromatic
DNA adducts and polymorphisms in metabolic genes in healthy adults: Findings from the EPIC-Spain cohort. Carcinogenesis
2009, 30, 968–976. [CrossRef]
38. Wang, L.N.; Wang, F.; Liu, J.; Ying-Hui, J.; Fang, C.; Ren, X.Q. CYP1A1 Ile462Val polymorphism is associated with cervical cancer
risk in Caucasians not Asians: A Meta-Analysis. Front. Physiol. 2017, 8, 1081. [CrossRef]
39. Haufroid, V.; Jakubowski, M.; Janasikb, B.; Ligocka, D.; Buchet, J.P.; Bergamaschi, E.; Manini, P.; Mutti, A.; Ghittorid, S.; Arande,
M.; et al. Interest of genotyping and phenotyping of drug-metabolizing enzymes for the interpretation of biological monitoring of
exposure to styrene. Pharmacogenetics 2002, 12, 691–702. [CrossRef]
40. Del Tredici, A.L.; Malhotra, A.; Dedek, M.; Espin, F.; Roach, D.; Zhu, G.D.; Voland, J.; Moreno, T.A. Frequency of CYP2D6 alleles
including structural variants in the United States. Front. Pharmacol. 2018, 9, 305. [CrossRef]
41. Windmill, K.F.; Gaedigk, A.; Hall, P.M.; Samaratunga, H.; Grant, D.M.; McManu, M.E. Localization of N-Acetyltransferases NAT1
and NAT2 in human tissues. Toxicol. Sci. 2000, 54, 19–29. [CrossRef] [PubMed]
42. Matejcic, M.; Vogelsang, M.; Wang, Y.; Parker, I.M. NAT1 and NAT2 genetic polymorphisms and environmental exposure as risk
factors for oesophageal squamous cell carcinoma: A case-control study. BMC Cancer 2015, 15, 150. [CrossRef] [PubMed]
43. Reynolds, W.F.; Hiltunen, M.; Pirskanen, M.; Mannermaa, A.; Helisalmi, S.; Lehtovirta, M.; Alafuzoff, I.; Soininen, H. MPO and
APO Eepsilon4 polymorphisms interact to increase risk for AD in Finnish males. Neurology 2000, 55, 1284–1290. [CrossRef]
[PubMed]
44. Reynolds, W.F.; Rhees, J.; Maciejewski, D.; Paladino, T.; Sieburg, H.; Maki, R.A.; Masliah, E. Myeloperoxidase polymorphism is
associated with gender specific risk for Alzheimer’s disease. Exp. Neurol. 1999, 155, 31–41. [CrossRef] [PubMed]
45. Mateo, I.; Sánchez-Juan, P.; Rodríguez-Rodríguez, E.; Infante, J.; Vázquez-Higuera, J.L.; García-Gorostiaga, I.; Berciano, J.;
Combarros, O. Synergistic effect of heme oxygenase-1 and tau genetic variants on Alzheimer’s disease risk. Dement Geriatr. Cogn.
Disord. 2008, 26, 339–342. [CrossRef]
46. Möllsten, A.; Marklund, S.L.; Wessman, M.; Svensson, M.; Forsblom, C.; Parkkonen, M.; Brismar, K.; Groop, P.H.; Dahlquist, G. A
functional polymorphism in the manganese superoxide dismutase gene and diabetic nephropathy. Diabetes 2007, 56, 265–269.
[CrossRef]
47. Honkura, Y.; Matsuo, H.; Murakami, S.; Sakiyama, M.; Mizutari, K.; Shiotani, A.; Yamamoto, M.; Morita, I.; Shinomiya, N.;
Kawase, T.; et al. NRF2 Is a key target for prevention of noise-induced hearing loss by reducing oxidative damage of cochlea. Sci.
Rep. 2016, 6, 19329. [CrossRef]
48. Okano, Y.; Nezu, U.; Enokida, Y.; Lee, M.T.; Kinoshita, H.; Lezhava, A.; Hayashizaki, Y.; Morita, S.; Taguri, M.; Ichikawa, Y.;
et al. SNP (-617C>A) in ARE-like loci of the NRF2 gene: A new biomarker for prognosis of lung adenocarcinoma in Japanese
non-smoking women. PLoS ONE 2013, 8, e73794. [CrossRef]
49. Teena, R.; Dhamodharan, U.; Ali, D.; Rajesh, K.; Ramkumar, K.M. Genetic Polymorphism of the Nrf2 promoter region (rs35652124)
is associated with the risk of diabetic foot ulcers. Oxid. Med. Cell Longev. 2020, 2020, 9825028. [CrossRef]
50. Liu, F.; Luo, L.; Wei, Y.; Wang, W.; Li, B.; Yan, L.; Wen, T. A functional NQO1 609C>T polymorphism and risk of hepatocellular
carcinoma in a Chinese population. Tumour Biol. 2013, 34, 47–53. [CrossRef]
Int. J. Environ. Res. Public Health 2023, 20, 912 15 of 15

51. Hsu, P.C.; Chen, C.C.; Tzeng, H.E.; Hsu, Y.N.; Kuo, C.C.; Lin, M.L.; Chang, W.S.; Wang, Y.C.; Tsai, C.W.; Pei, J.S.; et al. HOGG1
rs1052133 Genotypes and risk of childhood acute lymphoblastic leukemia in a taiwanese population. In Vivo 2019, 33, 1081–1086.
[CrossRef] [PubMed]
52. Chen, Y.; Li, T.; Li, J.; Mo, Z. X-ray repair cross-complementing group 1 (XRCC1) Arg399Gln polymorphism significantly
associated with prostate cancer. Int. J. Biol. Mark. 2015, 30, e12–e21. [CrossRef] [PubMed]
53. Smith, T.R.; Miller, M.S.; Lohman, K.; Lange, E.M.; Case, L.D.; Mohrenweiser, H.W.; Hu, J.J. Polymorphisms of XRCC1 and
XRCC3 genes and susceptibility to breast cancer. Cancer Lett. 2003, 190, 183–190. [CrossRef] [PubMed]
54. Salimzadeh, H.; Lindskog, E.B.; Gustavsson, B.; Wettergren, Y.; Ljungman, D. Association of DNA repair gene variants with
colorectal cancer: Risk, toxicity, and survival. BMC Cancer 2020, 20, 409. [CrossRef]
55. Li, D.; Zhao, H.; Gelernter, J. Strong association of the alcohol dehydrogenase 1B gene (ADH1B) with alcohol dependence and
alcohol-induced medical diseases. Biol. Psychiatry 2011, 70, 504–512. [CrossRef]
56. Thomasson, H.; Beard, J.D.; Li, T.K. ADH2 gene polymorphisms are determinants of alcohol pharmacokinetics. Alcohol Clin. Exp.
Res. 1995, 19, 1494–1499. [CrossRef]
57. Xue, Y.; Wang, M.; Zhong, D.; Tong, N.; Chu, H.; Sheng, X.; Zhang, Z. ADH1C Ile350Val polymorphism and cancer risk: Evidence
from 35 case-control studies. PLoS ONE 2012, 7, e37227. [CrossRef]
58. Xu, X.-L.; Wang, J.; Zhu, S.-M.; Yang, M.; Fang, Y.; Qian, S.; An, Z.; Mao., W. Impact of alcohol dehydrogenase gene 4
polymorphisms on esophageal squamous-cell carcinoma risk in a Chinese population. J. Clin. Oncol. 2015, 33 (Suppl. S15), e15021.
[CrossRef]
59. Chang, B.; Hao, S.; Zhang, L.; Gao, M.; Sun, Y.; Huang, A.; Teng, G.; Li, B.; Crabb, D.W.; Kusumanchi, P.; et al. Association
between aldehyde dehydrogenase 2 Glu504Lys polymorphism and alcoholic liver disease. Am. J. Med. Sci. 2018, 356, 10–14.
[CrossRef]
60. Denny, J.C.; Collins, F.S. Precision medicine in 2030-seven ways to transform healthcare. Cell 2021, 184, 1415–1419. [CrossRef]
61. Velmovitsky, P.E.; Bevilacqua, T.; Alencar, P.; Cowan, D.; Morita, P.P. Convergence of precision medicine and public health into
precision public health: Toward a big data perspective. Front. Public Health 2021, 9, 561873. [CrossRef] [PubMed]
62. Huang, T.; Shu, Y.; Cai, Y.D. Genetic differences among ethnic groups. BMC Genom. 2015, 16, 1093. [CrossRef] [PubMed]
63. Esteban, M.; Castaño, A. Non-invasive matrices in human biomonitoring: A review. Environ. Int. 2009, 35, 438–449. [CrossRef]
[PubMed]
64. Bergdahl, I.A.; Skerfving, S. Biomonitoring of lead exposure-alternatives to blood. J. Toxicol. Environ. Health A 2008, 71, 1235–1243.
[CrossRef]
65. Lum, A.; Le Marchand, L. A simple mouthwash method for obtaining genomic DNA in molecular epidemiological studies.
Cancer Epidemiol. Biomark. Prev. 1998, 7, 719–724.
66. Feigelson, H.S.; Rodriguez, C.; Welch, R.; Hutchinson, A.; Shao, W.; Jacobs, K.; Diver, W.R.; Calle, E.E.; Thun, M.J.; Hunter, D.J.;
et al. Successful genome-wide scan in paired blood and buccal samples. Cancer Epidemiol. Biomark. Prev. 2007, 16, 1023–1025.
[CrossRef]
67. Mold, A.; Beccaria, F.; Berridge, V.; Eisenbach-Stangl, I.; Herczyńska, G.; Moskalewicz, J.; Petrilli, E.; Taylor, S. Concepts of
addiction in Europe in the 1970s and 1980s: What does a long view tell us about drugs, alcohol, and tobacco? In Concepts of
Addictive Substances and Behaviours across Time and Place; Hellman, M., Berridge, V., Duke, K., Mold, A., Eds.; Oxford University
Press: Oxford, UK, 2016; pp. 15–32. [CrossRef]
68. Ghatak, S.; Muthukumaran, R.B.; Nachimuthu, S.K. A simple method of genomic DNA extraction from human samples for
PCR-RFLP analysis. J. Biomol. Tech. 2013, 24, 224–231. [CrossRef]
69. National Human Genome Research Institute. Available online: https://www.genome.gov/ (accessed on 2 September 2022).
70. Almazroo, O.A.; Miah, M.K.; Venkataramanan, R. Drug Metabolism in the liver. Clin. Liver Dis. 2017, 21, 1–20. [CrossRef]
71. Kielholz, P. Alcohol and Depression. Br. J. Addict. Alcohol Other Drugs 1970, 65, 187–193. [CrossRef]
72. Warner, K.E. Cigarette Smoking in the 1970’s: The Impact of the Antismoking Campaign on Consumption. Science 1981, 211,
729–731. [CrossRef]
73. Hahn, M.; Roll, S.C. The Influence of pharmacogenetics on the clinical relevance of pharmacokinetic drug–drug interactions:
Drug–gene, drug–gene–gene and drug–drug–gene interactions. Pharmaceuticals 2021, 14, 487. [CrossRef]
74. Krainca, T.; Fuentesa, A. Genetic ancestry in precision medicine is reshaping the race debate. Proc. Natl. Acad. Sci. USA 2022, 119,
e2203033119. [CrossRef] [PubMed]
75. Traversi, D.; Pulliero, A.; Izzotti, A.; Franchitti, E.; Iacoviello, L.; Gianfagna, F.; Gialluisi, A.; Izzi, B.; Agodi, A.; Barchitta, M.; et al.
Precision medicine and public health: New challenges for effective and sustainable health. J. Pers. Med. 2021, 11, 135. [CrossRef]
[PubMed]
76. Shah, R.R.; Gaedigk, A. Precision medicine: Does ethnicity information complement genotype-based prescribing decisions? Ther.
Adv. Drug Saf. 2018, 9, 45–62. [CrossRef] [PubMed]

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